ACRIN 6682 Phase II Trial of 64 Cu-ATSM PET/CT in Cervical Cancer Principal Investigator: Farrokh Dehdashti, MD 10/2/09

Background Tumor hypoxia is an important prognostic factor in cervical cancer and predicts for decreased overall and disease-free survival Hypoxic-measuring tools are needed: –To predict patient outcome –To select treatments on an individual basis –To evaluate early response to treatment

Measurement of Hypoxia with Cu-ATSM Copper labeled dithiosemicarbazone complex (Cu-ATSM) ( Fujibayashi et al.,1989, 1997; John et al., 1990; Taniuchi et al., 1995 ) –Highly lipophilic - high membrane permeability - high extraction –Reduced by bioreductive enzymes only in hypoxic cells (mitochondria in non-tumor and microsomal/cytosol in tumors) –Retained in hypoxic tissues, but rapidly washes out of normoxic tissues –Good hypoxic/normoxic tissue activity ratio (hypoxic/normoxic of 4.0 at 15 min)

Prelimiary Data 60 Cu-ATSM: Cervical Cancer –38 patients undergoing radiotherapy  chemotherapy –Pre-therapy 60 Cu-ATSM-PET (tumor/muscle ratio) –Response to therapy assessed (follow-up 3-79 months) Dehdashti et al., JNM 2008; 49:210

60 Cu-ATSM: Cervical Cancer Dehdashti et al., JNM 2008; 49:210

60 Cu-ATSM: Cervical Cancer FDG 60 Cu-ATSM T/M = 3.0 Responder T/M = 4.5 Non-responder Dehdashti et al., JNM 2008; 49:210 B=Bladder, P=Primary Tumor

60 Cu vs. 64 Cu-ATSM: Cervical Cancer Lewis, et al., JNM 2008; 49:1177 Half-life 60 Cu 23.7 min 64 Cu 12.7 hr Patients studied with 60 Cu-ATSM-PET and 64 Cu-ATSM-PET on 2 separate days (range days, averaged 5.8 days)

Specific Hypotheses 64 Cu-ATSM-PET/CT distinguishes patients with poorer survival rate from those with better survival rate prior to initiation of therapy 64 Cu-ATSM-PET/CT provides unique prognostic information different from that revealed by known prognostic factors in an invasive squamous cell cervical cancer Primary Objective To determine if higher 64 Cu-ATSM uptake is associated with lower progression-free survival Study Hypotheses and Objectives

Primary Endpoint: to assess the relationship between 64 Cu-ATSM uptake in the primary cervical tumor and progression-free survival after chemoradiotherapy. Secondary Endpoints: to assess the relationship between 64 Cu-ATSM uptake and: –overall survival –rates of local recurrence and development of distant metastasis –frequency of complete metabolic response by FDG-PET –tumor volume and the frequency of lymph node metastasis at diagnosis –markers of tumor hypoxia assessed by immunohistochemistry on biopsy tissue from the primary tumor ACRIN 6682 Endpoints

Pre-therapy clinical whole-body FDG-PET/CT Stages IB2 –IVA invasive squamous cell carcinoma, scheduled to undergo radiation therapy and concurrent cisplatin chemotherapy Pre-therapy pelvic 64 Cu-ATSM-PET/CT and analysis of tumor biopsy for hypoxic markers ACRIN 6682 Schema Concurrent chemoradiotherapy Clinical FDG-PET/CT three (3) months after completion of therapy Clinical follow-up for detection of recurrence and/or death N=100, enrollment period=18 months

Protocol approved by CTEP Amendments to WU IND for this protocol have been made Site ready for patient recruitment: Wash Univ. Sites close to opening the trial: Boston Medical, Fox Chase Potential sites: City of Hope LA, Duke Univ., Medical College of WI, MD Anderson, Indiana Univ. Medical Center, Johns Hopkins MI, Univ. of Iowa, Memorial Sloan-Kettering Cancer Center, Mt. Sinai NY, University of Wisconsin Hospital, Wayne State Univ. ACRIN 6682 Status

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